發(fā)布時(shí)間：2018-04-04 05:50

  本文選題：mTOR　切入點(diǎn)：Raptor　出處：《南京醫(yī)科大學(xué)》2017年碩士論文

【摘要】：雷帕霉素是重要的免疫抑制劑和腫瘤治療的臨床藥物,但已被報(bào)道能導(dǎo)致男性不育等一系列副作用。雷帕霉素的作用靶標(biāo)——mTOR信號通路是細(xì)胞內(nèi)重要的代謝調(diào)節(jié)中樞,主要通過形成兩種復(fù)合物mTORC1與mTORC2發(fā)揮其功能,在蛋白質(zhì)合成、糖代謝以及細(xì)胞骨架形成等眾多細(xì)胞功能中都扮演了重要角色。這些功能是確保精子發(fā)生正常進(jìn)行的重要基礎(chǔ)。減數(shù)分裂是生殖細(xì)胞獨(dú)有的細(xì)胞分裂方式,也是精子發(fā)生過程中至關(guān)重要的一環(huán),這一階段涉及到同源染色體的聯(lián)會與重組、性染色體沉默(MSCI)等一系列關(guān)鍵步驟,任何一步出錯(cuò)都可能引起減數(shù)分裂阻滯,從而導(dǎo)致生精障礙。但mTOR信號通路在雄性生殖細(xì)胞減數(shù)分裂中的具體作用及機(jī)制尚未被闡明。為了研究mTOR信號通路在雄性精子發(fā)生及減數(shù)分裂中可能存在的作用及分子機(jī)制,我們制備了由Ngn3-CRE介導(dǎo)的在生精細(xì)胞內(nèi)對mTORC1核心組分蛋白Raptor基因條件性敲除小鼠。通過對敲除小鼠的表型分析表明,Raptor的敲除導(dǎo)致減數(shù)分裂阻滯在粗線期精母細(xì)胞。進(jìn)一步的研究表明,雄性敲除小鼠減數(shù)分裂前期染色體的聯(lián)會和性染色體的沉默受到了影響。綜上所述,我們的研究結(jié)果證實(shí)了 mTORC1信號通路在雄性減數(shù)分裂和性染色體沉默中有不可替代的作用。這一發(fā)現(xiàn)不僅為雷帕霉素等mTOR抑制劑導(dǎo)致雄性不育提供了更充分的解釋,也有助未來開發(fā)特異性針對mTORC1信號通路的男性避孕藥。
[Abstract]:Rapamycin is an important clinical drug for immunosuppressant and tumor therapy, but has been reported to cause a series of side effects such as male infertility.The target of rapamycin, mTOR signaling pathway, is an important metabolic regulatory center in cells. It plays a role in protein synthesis by forming two complexes, mTORC1 and mTORC2.Glucose metabolism and cytoskeleton formation play an important role in many cellular functions.These functions are an important basis for ensuring normal spermatogenesis.Meiosis is a unique cell division of germ cells and a crucial link in spermatogenesis. This stage involves a series of key steps such as the conjunctions and recombination of homologous chromosomes, the silencing of sexual chromosomes, and MSCI.Any error in any step can lead to meiosis block, which can lead to spermatogenic disorder.However, the role and mechanism of mTOR signaling pathway in male germ cell meiosis has not been elucidated.In order to study the possible role and molecular mechanism of mTOR signaling pathway in male spermatogenesis and meiosis, we have prepared Ngn3-CRE mediated conditional knockout mice in spermatogenic cells on the mTORC1 core protein Raptor gene.Phenotypic analysis of the knockout mice showed that the knockout of Raptor caused meiosis to be blocked in the coarse line spermatocytes.Further studies showed that the synapsis and silencing of sex chromosomes in male knockout mice were affected.In conclusion, our results confirm that mTORC1 signaling pathway plays an irreplaceable role in male meiosis and sex chromosome silencing.The findings not only provide a fuller explanation for male sterility caused by mTOR inhibitors such as rapamycin, but also contribute to the development of future male contraceptives that specifically target the mTORC1 signaling pathway.
【學(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R698.2
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本文編號：1708637